Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 952479-65-1 | MDL No. : | MFCD22683960 |
Formula : | C9H8N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GEWJEKADAXWFPY-UHFFFAOYSA-N |
M.W : | 176.17 | Pubchem ID : | 24728931 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.37 |
TPSA : | 54.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 1.18 |
Log Po/w (XLOGP3) : | 1.41 |
Log Po/w (WLOGP) : | 1.35 |
Log Po/w (MLOGP) : | 1.04 |
Log Po/w (SILICOS-IT) : | 1.84 |
Consensus Log Po/w : | 1.36 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.2 |
Solubility : | 1.11 mg/ml ; 0.0063 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.17 |
Solubility : | 1.19 mg/ml ; 0.00678 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.98 |
Solubility : | 0.183 mg/ml ; 0.00104 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.54 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide; In methanol; water; at 0 - 20℃; for 18h; | A solution of the indazole (8.30 g, 33.0 mmol) in methanol (100 mL) at 0 C was treated with an 29percent aqueous solution of potassium hydroxide (20 mL). The reaction mixture was allowed to warm to rt and was maintained for 18 h. The pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid and the volatiles were removed under reduced pressure. The residue was partitioned between brine (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with additional warm ethyl acetate (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solids were isolated by filtration, thus providing 5.86 g (94percent) of the acid |
55% | A mixture of 2-amino-3-methylbenzoic acid (15.2 g, 0.10 mol), dimethylformamide (333 mL) and CsCO3 (49 g, 0.15 mol) was stirred at room temperature for about 40 minutes before drop wise addition of iodomethane (14.2 g, 6.2 mL, 0.10 mol) in dimethylformamide ("DMF") (115 mL). The mixture was stirred . at room temperature overnight. The mixture was diluted with water (1 L), and extracted with diethyl ether. The aqueous phase was back extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous NaCI, dried over MgSO4, filtered and concentrated. The resultant material was dried at room temperature/0.5 mmHg to afford methyl 2-amino-3-methylbenzoate (17 g, 100percent).To a solution methyl 2-amino-3-methylbenzoate (16.5 g, 0.10 mol) in CHCI3 (286 mL) was added acetic anhydride (23.5 g, 21.7 mL, 0.23 mol) so as to maintain the internal temperature <40 0C. The mixture was stirred at room temperature for 1 hour before addition of potassium acetate (2.94 g, 30 mmol) and isoamyl nitrite (25.8 g, 30 mL, 0.22 mol). The resultant mixture was heated at reflux overnight. To this was then added methanol (94 mL) and 6 N HCI (94 mL) and the mixture was stirred overnight. The reaction mixture was concentrated to provide an orange solid which was subsequently triturated with ethyl <n="29"/>acetate and the solids were isolated by vacuum filtration. The solids were dried at room temperature/0.5 mmHg to afford methyl 1 H-indazole-7-carboxylate (15.4 g, 88percent). -A solution of methyl 1 H-indazole-7-carboxylate (14.96 g, 84.9 mmol) in methanol (180 ml_) was cooled to 0 0C before addition of 29percent aqueous potassium hydroxide (36 ml_). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The pH was adjusted to 5.5 using concentrated HCI. The volatiles were removed by vacuum filtration and the resultant material was suspended in water (100 mL) and ethyl acetate (200 mL). The resultant precipitate was isolated by vacuum filtration and rinsed with ethyl acetate. The solids were dried at room temperature/0.5 mmHg to afford the title compound (7.54 g, 55percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a solution of the ester (17.5 g, 106 mmol) in chloroform (300 mL) was added acetic anhydride (22.6 mL, 239 mmol, 2.3 eq) while maintaining the temperature below 40 C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (3.00 g, 30.6 mmol, 0.3 eq) and isoamyl nitrite (30.6 mL, 228 mmol, 2.2 eqiv) was added. The reaction mixture was heated at reflux for 24 h and was allowed to cool to room temperature. The reaction mixture was washed with a saturated, aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100 mL) were added to the residue and the mixture was maintained for 18 h at rt. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The product was isolated by filteration, washed with ethyl acetate (20 mL), and dried to provide 15.3 g (68%) of methyl 1H-indazole-7-carboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) & delta 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177 (M+ +1) | |
47% | A cooled (5 C) solution of sodium nitrite (1.670 g, 24.21 mmol) in water (3.3 mL) was added to a cooled (0 C) solution of methyl 2-amino-3-methylbenzoate (4.00 g, 24.21 mmol) in 50% HBF4 (10 ml). After complete addition the mixture was stirred for 1 hour at room temperature. The resultant precipitate was isolated by filtration and washed with Et2O. The diazonium salt was then added in one portion to a stirred mixture of dried and powdered potassium acetate (4.752 g, 48.42 mmol) and 18-crown-6 (0.32 g, 0.4 mmol) in dry chloroform (40 mL). After 1 hour the precipitate was removed and the filtrate was washed with water (20 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from heptanes gave the title compound (2.017 g, 47%) as a pale orange powder. mp. 110 - 112 C. 1H NMR (300 MHz, CDCl3) delta 11.54 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 7.3, 1.0 Hz, 1H), 7.96 (ddd, J = 8.0, 1.5, 1.0 Hz, 1H), 7.21 (dd, J = 8.0, 7.3 Hz, 1H), 4.03 (s, 3H). 13C NMR (75 MHz, CDCl3) delta 166.7, 138.8, 135.0, 129.2, 126.8, 124.5, 120.5, 112.6, 52.5 | |
To a solution of methyl 2-amino-3-methylbenzoate (13g, 78.7 mmol) in 50OmL of AcOH at 0 0C was slowly added a solution of sodium nitrite (6.5g, 94.2mmol) in 10OmL of water dropwise over 1 hour. The solution was allowed to stir for ON at it afterwhich it was concentrated to one tenth its volume and then neutralized by the slow addition of 5% ammonium hyroxide. The solution was then extracted with EtOAc and the organic phases were then combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The indazole-methyl ester was purified by flash chromotography using 5-25% EtOAc/hexanes to yield 1Og of pure ester. 1H NMR (500 MHz, CDC13): delta 12.5 (bs, IH), 8.2 (s,lH), 8.1 (m, 2H), 7.3 (t, IH), 4.09 (s, 3H). LRMS M+l 177.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; isopentyl nitrite; In chloroform;Heating / reflux; | A mixture of 2-amino-3-methylbenzoic acid (15.2 g, 0.10 mol), dimethylformamide (333 mL) and CsCO3 (49 g, 0.15 mol) was stirred at room temperature for about 40 minutes before drop wise addition of iodomethane (14.2 g, 6.2 mL, 0.10 mol) in dimethylformamide ("DMF") (115 mL). The mixture was stirred . at room temperature overnight. The mixture was diluted with water (1 L), and extracted with diethyl ether. The aqueous phase was back extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous NaCI, dried over MgSO4, filtered and concentrated. The resultant material was dried at room temperature/0.5 mmHg to afford methyl 2-amino-3-methylbenzoate (17 g, 100%).To a solution methyl 2-amino-3-methylbenzoate (16.5 g, 0.10 mol) in CHCI3 (286 mL) was added acetic anhydride (23.5 g, 21.7 mL, 0.23 mol) so as to maintain the internal temperature <40 0C. The mixture was stirred at room temperature for 1 hour before addition of potassium acetate (2.94 g, 30 mmol) and isoamyl nitrite (25.8 g, 30 mL, 0.22 mol). The resultant mixture was heated at reflux overnight. To this was then added methanol (94 mL) and 6 N HCI (94 mL) and the mixture was stirred overnight. The reaction mixture was concentrated to provide an orange solid which was subsequently triturated with ethyl <n="29"/>acetate and the solids were isolated by vacuum filtration. The solids were dried at room temperature/0.5 mmHg to afford methyl 1 H-indazole-7-carboxylate (15.4 g, 88%). -A solution of methyl 1 H-indazole-7-carboxylate (14.96 g, 84.9 mmol) in methanol (180 ml_) was cooled to 0 0C before addition of 29% aqueous potassium hydroxide (36 ml_). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The pH was adjusted to 5.5 using concentrated HCI. The volatiles were removed by vacuum filtration and the resultant material was suspended in water (100 mL) and ethyl acetate (200 mL). The resultant precipitate was isolated by vacuum filtration and rinsed with ethyl acetate. The solids were dried at room temperature/0.5 mmHg to afford the title compound (7.54 g, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With lithium aluminium tetrahydride; In tetrahydrofuran; for 0.5h; | To a solution of <strong>[755752-82-0]methyl 1H-indazole-7-carboxylate</strong> (0.182 g, 1.033 mmol) in dry THF (10 mL) was added a 1.0M solution of LiAlH4 (2.1 mL, 2.10 mmol). The reaction was stirred for 30 minutes and then quenched by successive addition of water (210 muL), 15% NaOH (210 muL) and water (630 muL). The suspension was diluted with THF (10 mL) and there was added MgSO4. The suspension was stirred for 10 minutes and filtered. The filter cake was washed with EtOAc (10 mL) and CHCl3/MeOH (1:1, 10 mL) and the combined filtrates were evaporated under reduced pressure to afford the title compound (0.112 g, 73%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 8.05 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 6.9 Hz, 1H), 7.06 (dd, J =8.0, 6.9 Hz, 1H), 4.80 (2H, s). 13C NMR (75 MHz, DMSO-d6) delta 133.4, 133.3, 124.8, 122.9, 122.8, 120.1, 118.8, 59.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.6 g | With potassium acetate; acetic acid; isopentyl nitrite; In 1,2-dichloro-ethane; for 24h;Reflux; | Example 9 Compound 16 (20.0g, 0.103mol) in 1,2-dichloroethane was added 100mL, acetic acid 20mL, was added potassium acetate (2.0g, 0.021mol) was dissolved after stirring, isoamyl nitrite (24.1 g of, 0.206 mol), heated to reflux and reacted at this temperature for 24 hours, cooled to room temperature, the reaction was washed with saturated sodium carbonate solution, the solution was evaporated under reduced pressure, 80 mL of ethanol was added to the residual liquid, dropwise under ice after 10mL of concentrated hydrochloric acid was added, and stirred at this temperature for 2 hours, the solid was filtered off to give a pale yellow solid, the resulting solid was added 90 mL of ethyl acetate and saturated sodium carbonate solution was added 100mL, stirred for 1 hour, the organic phase liquid separation, the aqueous phase was washed twice with ethyl acetate (2 * 50mL), the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a pale yellow solid 12.6g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With quinoline; copper(l) iodide; sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 145℃; for 24h;Inert atmosphere; | Example 10 Under nitrogen atmosphere, Compound 17 (5.5g, 0.031mol), compound 12 (10.0g, 0.029mol) in N- methylpyrrolidone was added 70 mL, and added quinoline (400mg, 3.1mmol), sodium carbonate ( 7.7g, 0.073mol), cuprous iodide (450mg, 2.3mmol), was heated to 145 deg.] C for 24 hours, after to room temperature, insoluble matter was filtered off, the filtrate was added 140mL of water, solid precipitated solid was filtered off after drying under reduced pressure (45 ) 8 h to obtain a light yellow solid 9.1g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With quinoline; copper(l) iodide; sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 145℃; for 24h;Inert atmosphere; | Example 10 Under nitrogen atmosphere, Compound 17 (5.5g, 0.031mol), compound 12 (10.0g, 0.029mol) in N- methylpyrrolidone was added 70 mL, and added quinoline (400mg, 3.1mmol), sodium carbonate ( 7.7g, 0.073mol), cuprous iodide (450mg, 2.3mmol), was heated to 145 deg.] C for 24 hours, after to room temperature, insoluble matter was filtered off, the filtrate was added 140mL of water, solid precipitated solid was filtered off after drying under reduced pressure (45 ) 8 h to obtain a light yellow solid 9.1g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With quinoline; copper(l) iodide; sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 145℃; for 24h;Inert atmosphere; | Example 10 Under nitrogen atmosphere, Compound 17 (5.5g, 0.031mol), compound 12 (10.0g, 0.029mol) in N- methylpyrrolidone was added 70 mL, and added quinoline (400mg, 3.1mmol), sodium carbonate ( 7.7g, 0.073mol), cuprous iodide (450mg, 2.3mmol), was heated to 145 deg.] C for 24 hours, after to room temperature, insoluble matter was filtered off, the filtrate was added 140mL of water, solid precipitated solid was filtered off after drying under reduced pressure (45 ) 8 h to obtain a light yellow solid 9.1g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.1 g | With quinoline; copper(l) iodide; sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 145℃; for 24h;Inert atmosphere; | Example 10 Under nitrogen atmosphere, Compound 17 (5.5g, 0.031mol), compound 12 (10.0g, 0.029mol) in N- methylpyrrolidone was added 70 mL, and added quinoline (400mg, 3.1mmol), sodium carbonate ( 7.7g, 0.073mol), cuprous iodide (450mg, 2.3mmol), was heated to 145 deg.] C for 24 hours, after to room temperature, insoluble matter was filtered off, the filtrate was added 140mL of water, solid precipitated solid was filtered off after drying under reduced pressure (45 ) 8 h to obtain a light yellow solid 9.1g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 22℃; for 16h; | In a round-bottom flask equipped with a magnetic stir bar was suspended <strong>[755752-82-0]methyl 1H-indazole-7-carboxylate</strong> (1.0 equiv, Combi-Blocks, CAS 755752-82-0) and cesium carbonate (3 equiv) in DMF (0.71 M). This suspension was cooled to 0 C. and treated with neat 4-(trifluoromethoxy)benzyl bromide (1.2 equiv, Aldrich, CAS 50824-05-0) drop-wise over a period of 5 minutes. The resulting reaction mixture was allowed to 22 C. over 16 hours. The reaction was then carefully quenched with the addition of ice-water and extracted with tert-butyl methyl ether. The combined organic extracts were washed further with water and brine, dried over MgSO4, and filtered. Concentration of the filtrate thus obtained under vacuum furnished the crude reaction product as a golden yellow oil. Purification by column chromatography through silica gel on the Teledyne ISCO Rf eluting with 10% to 100% EtOAc in hexanes as a gradient afforded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 70℃; for 18h;Cooling with ice; | Into a reaction vail equipped with a magnetic stir bar was added 1-([1,1?-biphenyl]-4-yl)ethan-1,2,2,2-d4-1-ol (1.5 equiv), <strong>[755752-82-0]methyl 1H-indazole-7-carboxylate</strong> (1.0 equiv), triphenylphosphine (1.3 equiv) and THF (0.3 M). The mixture was cooled over an ice bath, added diisopropyl azodicarboxylate (1.2 equiv) dropwise and stirred for 10 minutes as the reactants dissolved. After this time, the cooling bath was removed and the mixture was heated at 70 C. for 18 hours. LC-MS indicated completion of reaction. The reaction mixture was loaded onto a silica gel pre-cartridge and dried. Purification by column chromatography through silica gel on the Teledyne ISCO Rf (gradient elution with 0% to 60% EtOAc in hexanes) afforded the desired product (28% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: polyphosphoric acid / 3 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: polyphosphoric acid / 3 h / 120 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: polyphosphoric acid / 3 h / 120 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 °C 5: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 2 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: polyphosphoric acid / 3 h / 120 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 °C 5: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 2 h / 100 °C 6: lithium chloride / N,N-dimethyl-formamide / 4 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: PPA / 3 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: PPA / 3 h / 120 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: PPA / 3 h / 120 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C 5: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 2 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 2: water; lithium hydroxide / methanol / 20 °C 3: PPA / 3 h / 120 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C 5: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 2 h / 100 °C 6: lithium chloride / N,N-dimethyl-formamide / 4 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C 2: sodium hydroxide; water / tetrahydrofuran / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C 2: sodium hydroxide; water / tetrahydrofuran / 70 °C 3: polyphosphoric acid / 16 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C 2: sodium hydroxide; water / tetrahydrofuran / 70 °C 3: polyphosphoric acid / 16 h / 100 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C 2: sodium hydroxide; water / tetrahydrofuran / 70 °C 3: polyphosphoric acid / 16 h / 100 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 1 h / 0 °C 5: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 1 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C 2: sodium hydroxide; water / tetrahydrofuran / 70 °C 3: polyphosphoric acid / 16 h / 100 °C 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 1 h / 0 °C 5: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 1 h / 100 °C 6: lithium chloride / N,N-dimethyl-formamide / 1 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; | 69.C Step C: 1-((2,3-Difluorophenyl)methyl-d2)-1H-indazole-7-carboxylic acid methyl ester (Compound 69.4) Compound 69.3 was dissolved in N,N-dimethylformamide, compound 1H-indazole-7-methyl carboxylate and cesium carbonate were added at room temperature, and heated to 60°C and stirred for 1 hour.Then the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine,Dry with anhydrous sodium sulfate. Filter, spin dry, and purify the residue to obtain compound 69.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; | 37.B Step B: 1-Benzyl-1H-indazole-7-carboxylic acid methyl ester (Compound 37.2) Compound 37.1 (460mg, 2.6mmol) was dissolved in 10mL of N,N-dimethylformamide solution, and benzyl bromide (670mg, 3.9mmol) and cesium carbonate (1.3g, 3.9mmol) were added.Under nitrogen protection, the reaction solution was stirred at 80°C for 2 hours. Add aqueous solution to quench the reaction, Extract three times with 100ml ethyl acetate, combine the organic phases, spin dry,The product was purified to obtain 37.2 (360 mg, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; | 41.B Step B: 1-(3-Fluorobenzyl)-1H-indazole-7-carboxylic acid methyl ester (Compound 41.2) Compound 41.1 (640mg, 3.6mmol) was dissolved in 20mL of N,N-dimethylformamide solution, and 3-fluorobenzyl bromide (1.02g, 5.4mmol), cesium carbonate (2.3g, 7.23mmol), nitrogen Protect and stir the reaction solution at 80°C for 2 hours. Add aqueous solution to quench the reaction,Extract three times with 100ml ethyl acetate, combine the organic phases, spin dry,Purification gave the product 41.2 (700 mg, 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.1% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; | 46.A Step A: 1-(2,3-Difluorobenzyl)-1H-indazole-7-carboxylic acid methyl ester (Compound 46.1) 1-(Bromomethyl)-2,3-difluorobenzene (1.6g, 7.7mmol) was dissolved in 20mL of N,N-dimethylformamide, and compound 41.1 (920mg, 5.2mmol) and Cesium carbonate (3.4g, 10.4mmol) was heated to 60°C and stirred for 1 hour.Then the reaction solution was poured into 200 mL of water and extracted three times with 30 mL of ethyl acetate.The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filter and spin dry,The residue was purified by column to obtain compound 46.1 (760 mg, yellow solid, yield: 48.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 69% 2: 25% | Stage #1: 1H-indazole-7-carboxylic acid methyl ester With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 1-Bromopentane In N,N-dimethyl-formamide at 20℃; for 16h; regioselective reaction; | General Procedure (B) General procedure: To a 50 mL round bottom flask was added the appropriately substituted indazole (1 mmol) andDMF (5 mL). The resulting solution was treated with Cs2CO3 (489 mg, 1.5 mmol) and allowed tostir at room temperature for a further 30 min. To the suspension was added alkylating reagent,R2-X (1.2 mmol), and the mixture was stirred at room temperature for a further 16 h. The reactionmass was diluted with EtOAc (20 mL) and washed with brine (40 mL), sat. aq. Na2S2O3 (10 mL)and brine (40 mL × 2). The organic layer was dried over MgSO4 and concentrated under reducedpressure to afford crude product which was further purified using wet flash columnchromatography to yield the corresponding N-alkylated indazole(s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 1H-indazole-7-carboxylic acid methyl ester With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: 1-Bromopentane In tetrahydrofuran at 50℃; for 24h; regioselective reaction; | General Procedure (A) General procedure: To an oven-dried 50 mL round bottom flask was added the appropriately substituted indazole (1mmol) and THF (5 mL). The resulting solution was cooled to 0 °C and treated with NaH (26 mg,1.1 mmol) and allowed to stir at 0 °C for a further 1 h. To the cooled suspension was addedalkylating reagent, R2-X (1.2 mmol). The mixture was heated to 50 °C for a further 24 h. Thereaction mass was treated with MeOH (2.5 mL) and concentrated under reduced pressure. Theresulting crude residue was dissolved in EtOAc (25 mL), washed with sat. aq. Na2S2O3 (10 mL),H2O (10 mL), and brine (10 mL). The organic layer was dried over MgSO4 and concentrated invacuo to give the crude product which was further purified using wet flash column chromatographyto furnish the corresponding N-alkylated indazole(s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3h; | 1.2 (II) Intermediate C-14: Preparation of methyl 3-iodo-1H-indazole-7-carboxylic acid Intermediate B-14 (1equiv), iodine (2equiv) and potassium hydroxide (4equiv) were added to DMF, and reacted at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction is over, it is quenched with saturated sodium sulfite solution, followed by suction filtration, water washing, and oven drying to obtain a white solid with a yield of 85%. |
85% | With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 12h; | A Method A: Synthesis of Intermediate 1-1 To a mixture of R-1 (3.5 g, 19.9 mmol) in DMF (30 mL) was added NIS (5.37 g,19.9 mmol). The mixture was stirred at rt for 12 h then water (40 ml) was added. The solid was filtered, and dried to afford 1-1 (5.0 g, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium hydroxide; iodine / N,N-dimethyl-formamide / 3 h / 20 °C 2: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 8h; | 1.1 (I) Intermediate B-14: Preparation of methyl 1H-indazole-7-carboxylic acid Raw material A (1equiv), methanol (1.5equiv), EDCI (1.5equiv), HOBT (1equiv) and DIEA (1.5equiv) were added to dry DMF in sequence, and reacted at room temperature for 8 hours, and the reaction was monitored by TLC. After the reaction was completed, it was extracted with EA, washed with water, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a white solid. The yield was 90%. |
[ 1092351-86-4 ]
Methyl 2-methyl-2H-indazole-5-carboxylate
Similarity: 0.86
[ 1071433-01-6 ]
Methyl 2-methyl-2H-indazole-6-carboxylate
Similarity: 0.86
[ 1186537-91-6 ]
Methyl 3-ethyl-1H-pyrazole-4-carboxylate
Similarity: 0.83
[ 1017782-45-4 ]
Methyl 3-(tert-butyl)-1H-pyrazole-4-carboxylate
Similarity: 0.81
[ 23170-45-8 ]
Methyl 3-methyl-1H-pyrazole-4-carboxylate
Similarity: 0.80
[ 1092351-86-4 ]
Methyl 2-methyl-2H-indazole-5-carboxylate
Similarity: 0.86
[ 1071433-01-6 ]
Methyl 2-methyl-2H-indazole-6-carboxylate
Similarity: 0.86
[ 131666-74-5 ]
Methyl 2-(1H-indazol-3-yl)acetate
Similarity: 0.76
[ 885519-98-2 ]
3-Formyl-1H-indazole-5-carboxylic acid
Similarity: 0.70
[ 26663-42-3 ]
2-(1H-Indazol-3-yl)acetic acid
Similarity: 0.70